Identification of a Primary Target of Thalidomide Teratogenicity

Thalidomide Teratogenicity Target In the late 1950s and early 1960s, thalidomide was prescribed to pregnant women as a cure for morning sickness, but it was then found to have developmental defects, most obviously, stunted limbs in thousands of babies. Although its use was banned worldwide, thalidomide has since been found to be a valuable treatment for a range of cancers, inflammatory disorders, and leprosy. Several hypotheses have been proposed, but the mechanism of action of thalidomide is unknown. Using zebrafish and chicken as animal models, Ito et al. (p. 1345) show that the protein cereblon is a primary target of thalidomide. Thalidomide exerts teratogenic effects by binding to cereblon and inhibiting associated enzymatic activity important for limb development. Knowing the mechanism of action of thalidomide should encourage the search for thalidomide derivatives without teratogenic activity. Thalidomide exerts its damaging effects by binding to cereblon and blocking its activity in limb development. Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.